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The HPA axis: Metabolic Distress and Hypothalamic Amenorrhea

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If it hasn’t been clear yet, the hypothalamic-pituitary-adrenal (HPA) axis is one of the leading contributors to poor reproductive health.  The pituitary gland tells the reproductive organs what to do, and the hypothalamus tells the pituitary gland what to do, and the adrenals produce cortisol which influences the activity of both the hypothalamus and the pituitary glands.  Yikes.

Hypothalamic amenorrhea– or the loss of menstruation via disturbance to the HPA axis–affects 5 percent of women of reproductive age.  Subclinical women I suspect double that number, at least.  Many problems emerge as a result of HPA axis dysregulation that do not go as far as HA.  If it does advance to that stage, recovery from HA requires the restoration of normal cortisol function, the normalization of glandular tissue, and also rectification of the hypothyroidism that usually follows from hypothalamic dysregulation.

The HPA axis is dysregulated by all types of stress.  Acute stress is handled fairly easily, as the HPA axis is typically stable and in fact built to optimize an individual’s response to stress.  But chronic stress is– as we are all well aware– half of one of Satan’s eyelashes away from downright insidious.

Yet chronic stressors are divided by themselves into even more particular categories: psychosocial stress on one hand, and metabolic distress on the other.  Psychosocial stress is caused by mental, emotional, and social factors.  Metabolic distress is caused by living in an energy deficit, which is in turn caused both by calorie restriction and excess exercise.  These two forms of stress affect the HPA axis via different mechanisms.  Yet it should be another obvious fact for you that psychosocial stress and metabolic distress almost always go hand in hand.

This post is going to focus on metabolic distress.  I’ll treat the psychosocial and how these two are interrelated in the following post.

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I talked a bit in my previous posts about the HPA axis and how different pathologies can emerge from hyper-activity of the axis and hypo-activity.  Metabolic distress pushes the axis in hyper activity, at least for as long as the system can handle it before burning out.

The pathology of Hypothalamic Amenorrhea in general

The point of the HPA axis is to metabolically mobilize individuals in stressful circumstances.  So in them, stress levels rise.   In one study, the degree of ovarian compromise women suffered was in a precise inverse relationship with observed cortisol levels.   That’s pretty amazing.  What the cortisol does is perform negative feedback on the hypothalamus, such that the hypothalamus releases GnRH (gonadotropin releasing hormone) in decreased quantities.  Without GnRH, the pituitary doesn’t get the signal to more of its own hormones.  These include LH and FSH, hormones that in turn signal to the ovaries how much estrogen they should be producing according what time of the cycle it is.  The Pituitary is also responsible for secreting thyroid stimulating hormone (TSH).  Ordinarily, TSH levels rise or fall  in response to changes in T3 and T4 levels in the blood.   In HA, the pituitary never receives these signals, so TSH levels do not increase when they should.    This leads to the HPA axis setting an altered hypothalamic set point: it decreases as much as what is seen in hospitalized patients who develop what is called “sick euthyroid syndrome.”    Additionally, due to HA, the secretory patterns of growth hormone, prolactin, and melatonin vary.  This is problematic for a wide variety of reasons, not  the least of which are sleep, tissue repair, and hormone development.

Exercise, weight loss, and metabolic distress

When compared with normally menstruating but sedentary women, amenorrheic athletes demonstrate less progesterone secretion, fewer LH pulses from the pituitary in a day, and higher cortisol levels.  Amenorrheic athletes that are anovulatory have the fewest LH pulses in a day of all groups of women and the highest cortisol levlesl despite comparable leves of exertion and fitness among these athletes and others.  This is all to say that athletes experience greater risk of amenorrhea.

Though both sorts of stress are important for the ovaries, there is no doubt that exercise and weight loss serve as stressors all their own.  In monkeys trained to run, it has been shown that caloric supplementation reversed the anovulation induced by training.  Interestingly, the monkeys did not spontaneously develop a compensatory increase in appetite and had to be bribed with colorful candy to consume more calories.   The HPA axis was downregulating their drives to eat.    Studies in women also indicate that exercise and weight loss cause anovulation, probably through decreased GnRH release.  One team of researchers, Louks and Thurma, quantified the amount of energy restricted (absent of psychosocial stress*) needed to impact GnRH release in normally menstruating women.  They fed the women an energy stasis of 45kcal/kg of mean body mass per day.  This amounts to approximately 2200 calories for a woman weighing 110 pounds.  They administered graded daily energy deficits of 10, 25, or 35 kcal/kg.  This yields absolute values for the 110 pound woman of 1750 calories per day, 1000 calories per day, and then, Yikes!, 500 calories/day.  An energy deficit of 33 percent showed no impact in LH pulse frequency after 5 days, and an energy deficit of 75 percent showed a 40 percent decrease in LH in 5 days.  I imagine that both of these numbers would be more signficiant with longer time periods. Much more significant.   For all energy deficits cortisol levels rose.    At the 75 percent reduction, cortisol levels rose by 30 percent.  For the women who had the lowest progesterone levels at the start of the study, the cortisol levels and reductions in LH were impaced the most.  Most women, I’d imagine, who enter into such deficits do not have them imposed, but rather choose them.  This indicates to me that they are under a great deal of stress as well, such that the “stressed” women tested in this study probably closer approximate the majority of real American women.

*(On the other hand, modest dietary restriction accompanied by small amunts of exercise greatly increased the proportion of monkeys who become anovulatory when presented with social stress.   Social stress is also a significant factor in amenorrhea.)

The question remains: Is it the stress of exercise or the energy deficit that alters LH pulsatility in exercising women? This key question has been answered maybe by controlled studies in which women undergo dietary caloric restriction imposed in the face of increasing exercise demands. It would appear that LH pulsatility is not disrupted by the stress of exercise but rather by reduced energy availability.   With increased calories, the women don’t experience as much LH disturbance as when they don’t meet their caloric needs.  Presumably, then, sufficient calorie ingestion would really help mitigate the problem for women suffering exercise-induced HA.   According to this one spate of studies.   Honestly, I’m not sold.  Muscle tear down and growth, and any repair that occurs on joints and other tissues, involves the activation of inflammatory responses.  Cortisol rides along with those.  If the exercise and the resulting cortisol is significant enough, supplementation with calories cannot cure everything.  Additionally, the psychosocial stress that accompanies excess exercise plays a role.  Additionally, thyroid function may be negative impacted by trying to make up for fluctuating caloric intake.  And finally, I find it implausible that women outside of controlled studies will know precisely how much they need to add to their diets in order to achieve the proper balance.

Nutriton and metabolism play critical roles in all of this.    (Note: the few studies done on men in this realm suggest that undernutritional is as deleterious to reproductive competency in men as it is in women.)  Metabolic imbalance occurs when energy expenditure exceeds energy intake, right?  This is important for our bodies, so there are many different (and redundant) signals to the brain from metabolic systems.  This makes it hard to suss out what system does precisely what, and which is the most important in studying these issues.  Signals reflecting energy stores, recent nutritional information, and specific classes of nutrients are integrated in the central nervous sytem, particularly the hypothalamus, to coordinate energy intake and expenditure.    Chronic energy deficiency alters thyroidal function to slow metabolism and correct negative energy balance.

Putative appetite suppressing and satiety signals include cortisol, CRH, insulin, glucose, resistin, leptin, proopiomelanocortin POMC, cocain- and amphetamine-regulated transcript CART peptide, peptide YY, and glucagon=like peptide 1.  (Yikes!)  The hormones from fat cells implicated in energy regulation include leptin, adiponectin, and resistin.  Leptin, which we all know and love, is the dominant long-term energy signal informing the brain of fat reserves– it is also a satiety signal.  It’s a big deal, and for women’s with HPA axis dysregulation, having lots of it, or at least good sensitivity to it, is helpful.   Adiponectin acts as an insulin-sensitizing agent by reducing hepatic (liver) glucose production.  This one, contra leptin, is reduced in obesity.  Resistin is linked to insulin tolerance and decreases glucose uptake by fat cells.  Ghrelin is produced by the gastrointestinal tract.  Plasma ghrelin levels rise during fasting and immediately before anticipated mealtimes and then fall within an hour of food intake, suggesting that ghrelin is important for meal initiation.

Resistin levels correlate with free cortisol levels, indicating that in states of stress the body is trying to sensitize the body to insulin.  Adoponectin correlates with insulin sensitivity, too, particulalry in studies of depressed humans.    In women, ghrelin levels increase in both anorexia nervosa and exericise amenorrhea.  No surprise there.   The greater the energy deficit, the more the body wants to eat.

Leptin is crucial.  Importantly, women who primarily suffer from psychosocial stress and not metabolic distress recover from hypothalamic amenorrhea without changing weight or leptin levels.   What this tells us is that leptin is mostly a problem for women who suffer energy deficits.   Studies of rodents as well as of women indicate that increasing leptin and leptin sensitivity induces regularity.  When mice are injected with leptin during a fast, for example, their cycles remain the proper length.   Without leptin, however, their cycles become longer and irregular.

Leptin is produced by fat cells.  Some other tissue produces it as well, but not as significantly.  Low body fat is a very significant problem for hypothalamic amenorrhea.   This is indicated by the fact that while many athletic women experience HA, women who participate in sports that require thinner physiques have much greater rates of HA.
Depending on the type of sport and competition level, the incidence of amenorrhea varies from 5 to 25%.   The rates of HA in sports that require low body weight are as high as 6-43 percent in ballet and 24-26 percent in long distance running. In less stringent sports, such ad bicycling and swimming, the rates of HA are both 12 percent.  All that is to say that low body fat is a clear signal that the body is running in an energy deficit.  When this is the case–that is, when the body is running at a deficit– it thinks its starving.  No, I’m sorry, it doesn’t think it’s starving.  It is starving.  So all of the satiation hormones– in this case ghrelin, resistin, and leptin– they muster their collective powers and try to get the body to eat more.    If that does not happen, and if leptin levels are too low, the hypothalamus will not receive the signal to start the reproductive hormone cascade.

 

All that said, the factors that cause, respond to and mitigate metabolically induced hypothalamic amenorrhea are many and complex.   In the end, they can almost be reduced to a leptin problem.  But leptin is an issue solely because of low body fat and energy deficits (*as well as any leptin insensitivity, which I will treat in another post).   There are also the issues of inflammation and stress that arises from exercise, as well as psychosocial stress–all of which build upon each other in the complex interactions between the HPA axis and the body at large.

In the following post, I’ll deal with psychosocial stress, and how these two are related.  Afterwards I will deal with recovering from hypothalamic amenorrhea.

 

 

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Managing director of Paleo for Women and author of Sexy by Nature.

36 Comments

  1. Looking forward to your post on HA recovery–currently working on it!

  2. Thanks for the briefing on HA, I’d never considered stress or energy deficit as that great of a potential factor in amenorrhea.

    This makes me think about other ways a person can end up in energy deficit, without necessarily overexercising or undereating. What if their body (or more specifically, their mitochondira) is inefficient, if (due to some nutritional deficiencies, for example,) is unable to extract as much energy from the foods they consume? ….

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  5. I was HA for nearly 7 years between the ages of 30-37. I am in no way underweight but because I was on this mission to loose weight, I would workout for 1.5 hours a day (and being naive, it was mainly cardio). Doctors are very ignorant about how to assist ladies with HA. I was told to put on weight, to go on the pill, to take estrogen, etc. etc. Nothing worked. Fortunately I was forwarded a study by another HA sufferer about a small study where women, very similar to myself, not thin but over-exercisers, were put on an extended clomid program for 3 months. So I convinced my doctor to let me do that, and low and behold, I started ovulating and having a period. I have never been so happy to see Ms. flow. And I am happy to stay that I have consistently had a period every month for the past 2 years. So there is hope out there but you have to be your biggest advocate and your own doctor!

    • Hi Ali… reading your post just gave me so much hope. I am 31 years old and last year I lost a significant amount of weight due to rigorous cardio exercise and a restricted diet. I worked with a nutritionist to get my intake to balance my output. I have gained a little over 10 pounds and my bmi is now 19.7. I went off the pill three months ago and still no period. I am so confused as to what the best thing to do is. I went to a reproductive endocrinologist and left feeling defeated. I would love to hear more about your road to recovery and to get some more advice. Would you be willing to email me at natalina427@gmail.com

      I’m really feeling at a loss here!

      Natalie

      • Give it time, love. Time and love and nourishment and stress reduction. And time. Did I say time? :)

    • Ali! I am a 31 yr old. I also have had HA for 7 years. I also found the study on the extended clomid protocol. I got a positive OPK test and still waiting to get period I am hoping this works. Have also cut back on intense exercise. Doing walking and yoga and eating mindfully and healthy. Any advice? What signs did you start to get around ovualtion and period? Would love to talk.

  6. This was a beautiful post. I really wish doctors knew more about this condition. I had no period between the ages of 22-27. I went to a dozen doctors, they either suggested the pill (I tried it for a couple of weeks and quit), or more blood exams, but no solution or explanation. I had decided that I just had to live with it. I am 5’4” and at that time my weight was between 97-100 pounds, through strict planned caloric intake (low fat/high carb) and exercise. To be perfectly honest, I was the happiest on that weight.
    I tried acupunture just for the fun of it, and it worked. I’m not sold on acupuncture though, so I wouldn’t suggest it to everyone, cause other factors changed as well in my life. First of all I gained weight. 108 pounds is the lowest weight my period returns. And at my current weight of around 112 pounds my periods are regular (at 34 years old). I am happy for that, especially after all that struggle of so many years, but I am not so happy with my current weight. Now I’m struggling with going back to being at least 108, so that I can still menstruate but also be happy with the way I look.
    Another issue I’d like to point out: I’ve had friends skinnier than me with regular periods all their lives. So it never occured to me that weight had anything to do with it. So a word of caution when comparing ourselves to others in issues of weight and health.
    To conclude, and to any girl still battling with this, I’d like to say that in most cases it is solved with a bit more calories and some weight, also sometimes a regular sex life helps, and maybe acupuncture might work for you too. And obviously the paleo way of eating. A note on that: even if I’m heavier, if I eat low fat I still skip periods, for maybe 3-4 months. Paleo regulates it in any weight.
    Thanks Stefani for this!

    • Are you on the paleo diet? Although you’re not thrilled about your current weight, do you find that it is stable? As in – you’re not gaining so much weight, just enough to be at a healthy, but still comfortable for you weight?

      • Yes I’m on the Paleo diet, and even though sometimes I don’t feel comfortable with my new weight, I always feel comfortable with my new body! Apart from the fact that my periods are stable now, which is a huge relief, my mood has also improved, which means I don’t get as depressed about it as I used to. Another huge factor is that I am more energetic and less hungry, and not needing too much food cause I hate the feel of a full stomach. And a last important thing I’d like to add: weight gain through the paleo diet puts weight on all the right places, so if this is combined with reasonable exercise, it will eventually lead to a better looking body! And to answer your question, yes my weight is now stable, around 112 pounds. Hope this helps, and good luck with everything! Trut me, you CAN feel better and be healthier!

  7. I have a question. If HA was caused by energy deficiency/metabolic stress, is there any indication on how long it might take for menstruation to resume after adequate weight gain back to normal? Is it possible for it to take more then a year with normal even more than normal body weight and calorie intake?

    • It’s different for all women, relying heavily on how much damage she has suffered, how much stress she is under, and the degree to which she succeeds in nourishing herself with nutrients and calroies moving forward.

  8. Hi.

    Can you point me in the direction of your article on recovering from hypothalamic amenorrhea?

    Thank you

  9. OK, I just need to know…

    I am anorexic (over-exerciser, but not too restrictive with my calories) If I switch to paleo, will I balloon to a size that I am not comfortable with because I have screwed up my leptin levels (and body, in general) as a result of HA?!? Or is this a way for me to simply get to a weight that my body is in balance in (i.e. not fatigued, regular menstruation)? I am trying to recover, but I need to do it my way and I cannot bare to do what I did last time when I was in recovery – just eat everything in my path, balloon up to a size I hated and develop a new eating disorder (bulimia)…
    I guess what I am saying is – for my to be comfortable with recovery, I need to know that I won’t be a version of myself that I hate…I want to be healthy, I want to have regular periods, and although I am slightly underweight now and know I need to gain some weight…I don’t want to “get fat”…
    PLEASE help me. Any words of advice or articles you can point me towards?!?!? I’m at the edge of my rope.

    • No, you won’t get “fat.” You can do it slowly and assure yourself overtime that what you’re doing is right for you body. As you feel better and continue to look just as good — if not even better, in my opinion, if you put on weight — then you’ll get more and more confirmation that it works for you. The whole trick to the evolutionary lifestyle is that you learn to trust your body and let it take care of itself. You are currently probably operating with strict control over your diet. But your body can do that, too, and powerfully, and probably even better than you can. And that is how you get your reproductive cycle back on track, too. Give your body food when it needs it, and it will show you that it has a real power to be full and be nourished and be fit all at the same time.

  10. I found this post really interesting and applicable to what I struggle with, but I feel like I’m only getting part of the story because I can’t find the post about recovery from HA. Can you give me some direction?

  11. I am also having a hard time locating the post about recovery from HA – can someone please tell me where to find it?

    • Everybody keeps asking. I never wrote it because it seemed the answer was obvious — eat more! :) I’ll perhaps throw one up in a couple of weeks.

      • Thanks, Stefani, for this summary. I’ve had HA for going on 4.5 years now, following the birth of my son. I’m at a ‘normal’ bodyweight and BMI, and the only thing docs can attribute it to is stress and poor energy availability.

        Anne Loucks, as you know, has written widely on the subject. Her studies find that 30 kcal per kg of fat free mass (ffm) of AVAILABLE energy (that needed before the costs of exercise) is the threshold at which LH pulsatility drops off, resulting in loss of menses.

        The intake needed for a health is 45 kcal per kg ffm (before the cost of exercise).

        Energy availability in athletes
        Anne B. Loucks a , Bente Kiens b & Hattie H. Wright c
        a Department of Biological Sciences, Ohio University, Athens, Ohio, USA
        b The Molecular Physiology Group, Department of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark
        c Center of Excellence for Nutrition, Faculty of Health Sciences, North-West University, Potchefstroom, South Africa
        Published online: 28 Jul 2011.

        Journal of Sports Sciences
        Publication details, including instructions for authors and subscription information:
        http://www.tandfonline.com/loi/rjsp20
        Energy balance and body composition in sports and
        exercise
        Anne B Loucks
        a Department of Biological Sciences, Ohio University, Athens, OH, 45701-2979, USA E-mail:
        Published online: 18 Feb 2007.

        • Fascinating, thank you!!

  12. I quit my birth control in March (with purposes of getting pregnant) and with no period after 4 months – my obgyn did an ultrasound. I was not ovulating. He believed it was HA (specifically Female Athlete Triad). He advised me to gain bodyfat, he wrote a 30 day Rx for premarin and set me on my way – I went back to ask about exercise because he hadn’t mentioned it. I do minimal cardio, but lift weights (bikini competitor) – only after I asked, he said to quit lifting. I want to maintain some muscle through pregnancy – and since he didn’t seem too sure of himself, I’d love to know your thoughts? My calories are way up – I’m gaining weight. But do I need to quit lifting completely?? Or can I keep it at a “maintenance level”?

  13. I found you through Just Eat Real Food on FB. She thought you might be able to help me.
    I am a 23 year old young woman who has been on birth control (different brands) for 9 years. I don’t think I’ve ever skipped a menstrual cycle before; usually I get it down to the minute every month. But the last 3 months a have fully skipped my cycle (not even spotting) and I can’t figure out why. Obviously the first month I took a pregnancy test and it came out negative. The second month my mom (a nurse) took a blood sample which proved I definitely wasn’t pregnant. Now i just skipped the third month and I’m still puzzled and worried. My doctor hasn’t given me a physical yet but she thought it had to do with my diet. The first month I was eating really poorly (totally off the paleo wagon) and then the second month I did the 21DSD. So both two months were extremes. But this third month I’ve been really good with my diet… So what gives? I haven’t been TOO stressed I don’t think. And I barely work out. Usually I just lift a couple weights and do my yoga stretches.

  14. Hi Stefani, thank you so much for this great post, but PLEASE can you also post what you know about HA and emotional stress. I have been suffering from HA since 2005, just after giving birth to my son. 6 weeks after birth I have had an Implanon birth control inserted but taken out after 2 years since the Implanon really impacted my moods. anyway, even once the Implanon was gone, my periods did not come back and eventually after a dozen different doctors, I got the HA diagnosis. well, I tried ‘relaxing”, drugs, acupuncture etc. all to no avail. you are the first person I come across who states that there is something like emotionally induced HA. PLEASE can you let me know more about it. Kindly yours,
    Nathalie

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  16. Hello. Two years ago both my husband and mother died. My husband suffered greatly during his death and as a result of caring for him, I did as well. I lost about 20 pounds in the month after his death. Then I started binge eating – though not purging. Over the course of 1 year, I gained 70 pounds. About 6 months into the binging, my periods stopped. The stress and trauma of grieving is still something I deal with, as is disordered eating (though no longer binging).

    Is it possible that this could cause HA in me? Much of the dialogue here is centered on underweight causes. What about significant stress and being overweight? Thank you for your response! Nadia

    • Yes! Totally possible. And my deepest, deepest, deepest condolences, Nadia.

      • Thank you! Your site has taught me a lot. I plan to get your ebook soon and continue to learn more about the paleo diet! Your reassurance is much appreciated.

    • Hi Nadia,
      I am so sorry to read what you have and still are going through. To your question about the weight. Well I seem to be like you, more on the overweight than under-weight side of things. It seems to me that the emotional stressors are in our case the trigger factors of HA and not the physical stressors. Unfortunatly this rules the “easy” eat more solution out for us. I have now been living with HA for 9 years and have given up hope to recover :-(.

      • Thanks for sharing with me. It is certainly a frustrating thing to deal with and understand. It has been 14 months for me… I have just found the paleo diet and plan to spend the next few months learning and implementing it.

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  18. Hi. I got HA in 2003. At that time I over exercised and for sure under ate. I don’t know what my BMI was at the time but I’m sure it was low. Fast forward, we now have 2 boys through the use of Endocrinology/Fertility docs. We are ready to begin trying for another child and will start with the docs help one week from today. I’m extremely grateful for all they have done but I can’t help wonder why my period has not returned. My life consistently over the past 5 years I have exercised between 4-6 hrs a week over 3-5 times per week. I eat 2200+ daily. I am not stressed. (Other than having two little dudes to keep up with on a daily basis – lol!) I have been pseudo-paleo because I eat more carbs than most, but am GF for 2 yrs now. I don’t eat prepackaged GF stuff but do make a lot of my own homemade baked yummy treats. And I cheat about once a week – that’s life. My BMI is now (and has been for years) 21.7. I don’t have PCOS – I’ve been tested and confirmed HA recently again. I don’t get it. I did however nurse both boys for 14 months. How long should I wait to see if I get my period back or should we just go ahead with medicine again to conceive? Oh, and I get pretty good sleep. In bed by 9/930PM and up at 6AM w/o alarm because I’m jus t ready to get up. Have you heard of a case like mine? Suggestions?

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